The present invention provides specific methods of using and administering etanercept to improve cognitive function in a human, for both the treatment and prevention of cognitive impairment, or, alternatively, to enhance cognitive function including Alzheimer's Disease, Idiopathic Dementia, and Traumatic Brain Injury. The methods of the present invention include the perispinal administration of etanercept. For the purposes of this patent "perispinal" is to be considered as referring to "perispinal extrathecal;" therefore direct intrathecal administration is excluded. Perispinal administration leads to enhanced delivery of etanercept to the brain in a therapeutically effective amount, via the vertebral venous system and/or the cerebrospinal fluid. Delivery of etanercept to the brain utilizing the methods of the present invention includes the use of the vertebral venous system to deliver etanercept to the brain via retrograde venous flow. Physical maneuvers are used to enhance delivery of etanercept to the brain via this route.

SUMMARY OF THE INVENTION

The present invention provides specific methods of using and administering etanercept to improve cognitive function in a human, for both the treatment and prevention of cognitive impairment, or, alternatively, to enhance cognitive function in three different broad categories of conditions: 1. Cognitive impairment which is characteristic of certain neurological disorders (for example Alzheimer's Disease, Idiopathic Dementia, and Traumatic Brain Injury); 2. Cognitive impairment which accompanies certain systemic or localized non-neurological conditions which are known or suspected to be associated with increased TNF (for example rheumatoid arthritis, psoriasis, and cancer cachexia); and 3. To enhance cognitive function in individuals in whom there is either no brain pathology or in whom the existence of brain pathology is either unknown or undefined, including a human without known disease.

The pathological conditions included in category 1 above include dementia or cognitive impairment suspected or established to be due to Alzheimer-type pathology, including Mild Cognitive Impairment, Possible Alzheimer's Disease, Probable Alzheimer's Disease, Alzheimer's Disease, and Senile Dementia/Alzheimer's type; Idiopathic Dementia or Dementia of unknown cause; Dementia with Lewy Bodies, also called Diffuse Lewy Body Disease; Picks Disease and other forms of frontotemporal dementia; cognitive impairment due to traumatic brain injury; AIDS (HIV) Dementia and Vascular Dementia. Cognitive impairment known to be due to infectious agents other than HIV or to brain tumors, either primary or metastatic, are not the subject of this patent.

Category 2 conditions include those medical conditions known to be associated with increased TNF, and specifically include rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis, and, in addition, cancer cachexia or cancer metastatic to the spine. Also included Category 2 is chronic back pain.

Category 3 includes normal individuals, without a known disease or disorder that has been established to be associated with elevated levels of TNF, who desire to achieve enhanced cognitive function.

The methods of the present invention include not only the perispinal administration of etanercept (which itself can be accomplished in various ways, including transcutaneous interspinous injection, or catheter delivery into the epidural or interspinous space) but also other novel methods of localized administration, specifically including intranasal administration. For the purposes of this patent "perispinal" is to be considered as referring to "perispinal extrathecal"; therefore direct intrathecal administration is excluded from the methods discussed.

Perispinal administration involves anatomically localized delivery performed so as to place the therapeutic molecule directly in the vicinity of the spine, and, for the purposes of this patent, administration which is outside of the intrathecal space (although subsequent movement of the therapeutic molecule into the intrathecal space does occur). Perispinal administration includes, but is not limited to, the following types of administration: parenteral; subcutaneous; intramuscular; interspinous; epidural; or peridural, and specifically includes the use of interspinous injection carried through the skin in the midline of the neck or back, directly overlying the spine; or administration via an indwelling epidural catheter, or via an indwelling catheter which delivers etanercept to the interspinous space. Perispinal administration leads to enhanced delivery of etanercept to the brain in a therapeutically effective amount, via the vertebral venous system and/or the cerebrospinal fluid. Delivery of etanercept to the brain utilizing the methods of the present invention includes the use of the vertebral venous system to deliver etanercept to the brain via retrograde venous flow. In addition to percutaneous injection into the interspinous space, etanercept may also be delivered to the interspinous or epidural space by implantable catheter, with the catheter reservoir placed remotely, such as in the abdominal area. Physical maneuvers are used to enhance delivery of etanercept to the brain via this route.

In addition to etanercept there are two non-monoclonal antibody biologic TNF binding proteins of consideration in this patent: onercept (Serono) and pegylated soluble TNF receptor type 1 (Amgen).

This invention is distinguished from the prior art in a variety of ways, including the use and description of novel and useful new uses, methods of use, and concepts involving TNF binding biologics, including: 1. Novel uses of TNF binding biologics to improve cognitive impairment or produce cognitive enhancement; and 2. Novel methods of use of TNF binding biologics; and 3. Novel concepts, including: a. Perispinal (extrathecal) administration distinguished from systemic forms of administration and intrathecal administration; b. The use of non-monoclonal antibody anti-TNF biologics as distinguished from the use of monoclonal antibody TNF biologics; c. Intranasal administration of TNF binding biologics as a method of delivery to the CNS; d. The use of TNF binding biologics to reduce cognitive impairment; e. The use of TNF binding biologics for cognitive inhancement; f. The use of the vertebral venous system to deliver therapeutic molecules to the brain; g. The use of physical maneuvers to facilitate delivery of therapeutic molecules to the brain; h. The use of physical maneuvers to influence the direction of venous flow within the cranio-vertebral venous system and thereby deliver therapeutic molecules to the site of neuronal inflammation; i. The use of retrograde venous perfusion to deliver therapeutic molecules to the brain, dorsal root ganglion, nerve roots, and spinal cord; j. The use of retrograde venous perfusion via the cranio-vertebral venous system to allow therapeutic molecules to bypass the blood-brain barrier and therefore reach the brain; k. The use of defects in the ligamentum flavum to facilitate delivery of perispinally administered etanercept to reach the epidural space; l. The use of the cranio-vertebral venous system as a "back door" to facilitate delivery of therapeutic molecules to the brain, brainstem, meninges, spinal cord, dorsal root ganglion, and nerve roots; m. The use of perispinal administration to introduce etanercept into the interspinous space or the epidural space to enable etanercept to reach the vertebral venous system; n. The use of perispinal administration to introduce etanercept into the interspinous space or the epidural space to enable etanercept to reach the cerebrospinal fluid; o. The use of etanercept, a dimeric fusion protein, as distinguished from a simple soluble TNF receptor, to produce prolonged improvement in cognitive function; p. The use of etanercept delivered by perispinal administration to produce cognitive improvement or to slow disease progression in certain neurological disorders characterized by progressive dementia and TNF-mediated brain inflammation (such as Alzheimer's Disease); q. The use of etanercept delivered by intranasal administration as a method to enable it to cross the blood-brain barrier and thereby be used to improve cognitive function.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Perispinal administration is a novel new delivery method for etanercept for improving cognitive function.

For the purposes of this discussion, "perispinal" means in the anatomic vicinity of the spine, but outside of the intrathecal space. For this discussion "anatomic vicinity" is generally defined as within 10 centimeters, or functionally defined as in close enough anatomic proximity to allow the therapeutic molecules of consideration herein to reach the spine and/or the subarachnoid space surrounding the spinal cord in therapeutic concentration when administered directly to this area without necessitating direct intrathecal delivery. For the treatment of brain disorders, such as Alzheimer's, perispinal administration is effective because it delivers the biologic to the CNS in a therapeutic amount. The predominant method by which this is accomplished is through enhanced delivery of the therapeutic molecule to the brain via the vertebral venous system and/or to the brain via the cerebrospinal fluid. This occurs without direct intrathecal injection, but rather by direct transport utilizing a vascular route (the vertebral venous system) or by diffusion from the interspinous or epidural space into the subarachnoid space. This enhanced delivery of etanercept into the cerebrospinal fluid is facilitated by delivery of etanercept to the epidural space, either by direct placement, or by perispinal administration. Midline gaps in the ligamentum flavum will facilitate delivery of etanercept administered by midline percutaneous interspinous injection to the epidural space. Etanercept in the epidural space may then be delivered into the vertebral venous system, with subsequent delivery to the brain or into the cerebrospinal fluid. Excess TNF, at levels 25 times that of controls, has been documented in the CSF of patients with AD and MCI.

Perispinal administration of etanercept is accomplished by one of several preferred routes. The first is needle injection into the interspinous space. Etanercept is delivered to the interspinous space, in anatomic proximity to the ligamentum flavum, by midline interspinous needle injection. Midline defects in the ligamentum flavum are common, particularly in the cervical region. When present the midline ligamentum flavum defect provides a direct route of access for etanercept to the epidural space. Alternatively etanercept may be delivered directly into the epidural space by either direct epidural injection through the ligamentum flavum utilizing a syringe and needle; or by use of an indwelling catheter placed within the epidural space; or may be delivered into the epidural space by venous carriage via the subcutaneous veins and/or the external vertebral venous plexus. A catheter with a delivery lumen placed in the epidural or interspinous space can be connected to a pump, which may be placed remotely, such as in the abdominal area. Within the epidural space lies a richly interconnected vertebral (epidural) venous plexus, which is valveless and which is capable of transporting etanercept rapidly in the cephalad or caudad directions. This epidural venous plexus is directly connected to veins which perforate the ligamentum flavum and which drain the interspinous space; thus etanercept delivered into or adjacent to the interspinous space may drain into a communicating vein and thereby into the epidural venous plexus. Etanercept may thereby diffuse in both a caudad and cephalad direction via this venous network, and may therefore rapidly (within minutes) exert a widespread therapeutic effect on TNF-mediated processes which affect the nerve roots, dorsal root ganglia, and spinal cord at multiple spinal levels, or, of even greater relevance to this invention, the brain. Physical maneuvers are utilized to facilitate venous carriage of etanercept to the brain via the VVS. Additionally this epidural venous plexus is interconnected with the endoneurial vascular network, and etanercept thereby may gain access to the endoneurial space and the cerebrospinal fluid, crossing the dura utilizing this direct vascular access route. Additionally, once etanercept has gained access to the epidural space it may directly diffuse into the endoneurial space through the capsule of the dorsal root ganglion, which may present a less efficient barrier to macromolecules than the dural barrier of the spinal nerve roots.

Perispinal administration of etanercept is generally performed in a blind fashion, to deliver etanercept into either the interspinous space or the epidural space. Delivery of etanercept into the interspinous space results in subsequent delivery of etanercept into the vertebral venous system because the interspinous space is drained by subcutaneous veins and other veins which directly connect to the external vertebral venous plexus portion of the VVS. Etanercept delivered to the interspinous space also diffuses into the epidural space and into the CSF.

Placement of an indwelling catheter in the epidural or interspinous space is less technically difficult than placement within the subarachnoid space, and has additional advantages. For example the risk of infection is lower. And the risk of CSF fluid leak and resulting headache is lower.

Perispinal administration for delivery of neuroactive molecules other than etanercept, including biologics, cytokines, anti-cytokines, hormones or drugs via the vertebral venous system, in a manner similar to that outlined herein, may be performed. The neuroactive compounds include erythropoietin; GDNF; BDNF; NGF; human growth hormone; Kineret.RTM. (IL 1-RA); anti-IL-6; ABX-EGF and other compounds with CNS activity. Concurrent patent applications involving these other therapeutic molecules delivered through the CVVS are in development by the inventor.

Localized administration for the treatment of localized clinical disorders has many clinical advantages over the use of conventional systemic treatment. Locally administered medication after delivery diffuses through local capillary, venous, arterial, and lymphatic action to reach the anatomic site of pathology, or, alternatively, to reach the cerebrospinal fluid (CSF). In addition local administration of a biologic in the vicinity of the spine (perispinal administration) has the key advantage of improved delivery of the agent to the central nervous system (CNS), in most cases via the vertebral venous system (VVS) or via the CSF.

A specific anatomic route, by which etanercept delivered by perispinal administration reaches the brain, has been defined by the inventor. This route is as follows. Etanercept is delivered to the interspinous space in proximity to the ligamentum flavum by percutaneous injection through the skin by midline interspinous needle injection, or by way of an indwelling catheter whose distal lumen lies within the interspinous space. Etanercept delivered to the interspinous space (being the anatomic region in the midline of the back, in between two adjacent spinous processes) may directly enter the vascular system (predominantly venous) which drains the interspinous space and which veins communicate directly with the vertebral venous plexus. Alternatively etanercept delivered to the interspinous space may reach the epidural space via a defect in the ligamentum flavum. Midline defects in the ligamentum flavum are common, particularly in the cervical region. When present the midline ligamentum flavum defect provides a direct route of access for etanercept to the epidural space. Alternatively etanercept may be delivered directly into the epidural space by either direct epidural injection through the ligamentum flavum utilizing a syringe and needle; or by use of an indwelling catheter placed within the epidural space. Such catheter can be connected to a pump, which may be placed remotely, such as in the abdominal area. Within the epidural space lies a richly interconnected epidural venous plexus, which is valveless and which is capable of transporting etanercept rapidly in the cephalad or caudad directions (see Batson references 48 and 49). The epidural venous plexus communicates with the intracranial venous network and therefore provides direct access of biologics to the brain, via retrograde flow, which is facilitated by gravity when the patient is placed in certain positions. Specifically the epidural veins communicate with the basivertebral vein, the intracranial sigmoid, occipital, and basilar venous sinuses, and the azygous system (see references 44 50). Additionally the epidural venous plexus is interconnected with the endoneurial vascular network, and etanercept thereby may gain access to the endoneurial space and the cerebrospinal fluid, crossing the dura utilizing this direct vascular access route. Additionally, once etanercept has gained access to the epidural space it may directly diffuse into the endoneurial space through the capsule of the dorsal root ganglion, which may present a less efficient barrier to macromolecules than the dural barrier of the spinal nerve roots. TNF-alpha has been demonstrated to be 25 times elevated compared with normal controls in the cerebrospinal fluid in certain individuals with cognitive impairment and Alzheimer's Disease (see Tarkowski references 11 and 12). In the present invention, etanercept which reaches the cerebrospinal fluid will immediately bind (and inactivate) TNF circulating in the CSF and therefore immediately reduce its adverse biologic effects on the brain.

The inventor is using the vertebral venous system as a non-obvious route of administration for the inventions disclosed herein. For a venous system is routinely conceptualized as a system that drains blood from a target area or organ. For example the venous system which drains the kidneys is widely acknowledged to be a vascular system that drains blood from the kidneys, not as a way of delivering a therapeutic molecule to the kidneys. Likewise the venous system of the brain, which is normally recognized as the jugular venous system, is widely medically recognized as a system which functions to drain blood from, not to, the brain. The present invention is counter-intuitive as it uses the venous system to deliver a therapeutic molecule to the brain. Likewise the use of the vertebral venous system (which the inventor proposes is a misnomer, and alternatively suggests should be designated as the cranio-vertebral venous system) to achieve delivery of therapeutic compounds to the brain, spinal cord, dorsal root ganglion, or nerve roots is not obvious, because conventional thinking is that this venous system functions to drain venous blood away from these anatomic sites. Therefore the inventions disclosed here are in this way counter-intuitive, because they rely on the cranio-vertebral venous system to deliver therapeutic molecules (including specifically etanercept) to the brain, brainstem, meninges, spinal cord, dorsal root ganglion, and nerve roots. This delivery is accomplished by inducing retrograde venous flow (the opposite direction from the usual direction), which is made possible by the lack of valves in this venous system, and by the proper use of gravity and positioning of the patient so that venous flow in the retrograde direction is accomplished. The rich connections between the cranial venous system and the vertebral venous system was beautifully depicted in 1828 by Breschet (reference 56), and a detailed discussion of this interconnection was made by Batson in 1940 and thereafter. The inventor has found a single intact copy of the Breschet plates, which are life-size and hand colored, in the special collections of the National Library of Medicine and has arranged for these to be photographed. A copy of plate 5 from this collection is included as an exhibit for this patent (FIG. 1), and illustrates the anatomical connection between the cranial and vertebral venous systems, an anatomic route which remains largely unrecognized by the medical community despite its careful depiction more than a century and a half ago.

The vertebral venous system is continuous along the length of the spine, but is, of course, closest to the brain in the cervical (neck) region. The vertebral venous plexus is extensive in the cervical region, and in this area defects in the ligamentum flavum are also more common, both of which factors help etanercept delivered to the cervical interspinous space to reach the brain. For all of these reasons, for this invention the usual point of injection for perispinal etanercept is in the posterior neck, overlying the spine. (As an alternative, perispinal administration of etanercept into the interspinous space can also be performed in the lumbar or thoracic regions since the vertebral venous system is continuous).

Correct positioning of the patient so as to facilitate retrograde blood flow in the cranial direction is utilized as part of the present invention to achieve improved delivery of etanercept to the brain. After a posterior cervical interspinous injection of etanercept in sterile water the patient is rapidly placed in the prone position and then the plane of the examining table is placed head-downward (Trendelenburg) to facilitate retrograde delivery to the brain and the cranial venous system. Etanercept, because of its biologic nature, is uniquely suited to delivery via the CVVS to the brain, because of its nearly instantaneous therapeutic effect. This instantaneous effect is the direct consequence of the fact that etanercept, in contradistinction to synthetic drugs which are not of biologic origin, does not function by influencing intermediary processes, but rather binds directly to soluble TNF. Therefore prolonged bathing of the target tissue by the therapeutic molecule is not necessary. Excess TNF is thereby rapidly bound and its adverse physiologic effects are immediately interdicted, including its adverse effects upon cognition.

The cranio-vertebral venous system is both anatomically and physiologically distinct from the venous system which drains the abdomen and thorax, which has been designated by others as the intracavitary venous system, with the cranio-vertebral venous system designated as the extracavitary venous system. Other nomenclature for the CVVS also comes to mind, such as the valveless venous system, or the bi-directional venous system, but they are perhaps less suitable than the CVVS. CVVS, of course, neglects to include the pelvic venous system, to which the CVVS is caudally connected, which would make the proper designation the CVPVS; but for purposes of this patent the inventor chooses to use the CVVS or VVS to emphasize the aspects of this invention which are deserving of the most attention. The CVVS and the intracavitary venous system do share anastomoses, as has been discussed at length by Batson. Batson has also described the retrograde flow possible with the VVS, but has not proposed the possible use of the VVS as a route to deliver therapeutic compounds to the brain, nor has anyone else. Again, this retrograde route of delivery is uniquely possible utilizing the VVS because of the lack of venous valves. In the present invention the CVVS is especially important for the rapid transport of etanercept to the brain of the human with changes in posture.

Placement of an indwelling catheter in the epidural space, or, alternatively, in the interspinous space, is less technically difficult than placement within the subarachnoid space, and has additional advantages. For example the risk of infection is lower. And the risk of CSF fluid leak and resulting headache is lower or nonexistent. The methods of the present invention are therefore distinguished from direct intrathecal administration of etanercept.

Etanercept has many biologic effects. Etanercept, for example, in addition to being a potent anti-inflammatory also has important anti-apoptotic effects which may be of particular importance in treating neurodegenerative diseases, such as Alzheimer's Disease, where apoptosis plays a pathogenetic role.

Biologics have been developed which have been shown to offer dramatic clinical benefit for systemic illnesses in humans, even for those disorders which have not responded to large and repeated doses of corticosteroids. These biologics fall into the category of cytokine antagonists because they block, or antagonize, the biologic action of a specific cytokine which has adverse clinical effects. For the purposes of this discussion, "antagonist", "inhibitor", and "blocker" are used interchangeably.

Perispinal delivery can also be used to deliver other types of therapeutic agents to the brain, cerebrospinal fluid, spine, or spinal cord. These therapeutic agents include pharmacologic agents or other cytokine antagonists. Perispinal delivery, however, is particularly advantageous when biologics, such as etanercept, are administered because of their efficacy at extremely low concentration (high biologic potency).

A detailed example of perispinal administration of etanercept utilizing an indwelling epidural catheter follows: An indwelling sterile catheter whose distal lumen lies within the epidural space is surgically implanted in a human with Alzheimer's Disease. During the surgical procedure the proximal end of the catheter is attached to a battery-powered pump which contains a reservoir containing 10 ml of etanercept in sterile water (10 mg/ml). The pump is surgically implanted in the abdomen during the same procedure in which the epidural catheter is implanted. The reservoir pump is positioned in the subcutaneous space with orientation and placement such that the reservoir is accessible to replenishment by percutaneous injection. The etanercept solution may be replenished by percutaneous injection periodically, because the reservoir has a port covered by a material, such as latex or a similar material which is penetrable by needle injection but which will self-seal once the needle is withdrawn. The pump is set to deliver etanercept at a rate of 20 mg per week. Therefore it will need to be refilled once every five weeks. The patient returns to the physician's office once every five weeks for the etanercept solution to be refilled by percutaneous instillation of etanercept solution.

One of the advantages of perispinal delivery into the interspinous space is that administration is simplified. This route is simple and safe. Hemorrhage due to the use of long or large bore needles is minimized because perispinal administration, by the subcutaneous route, requires only a short, narrow bore needle. Time-consuming and difficult epidural injection is not necessary. Epidural needle injection, for the purposes of this patent, is also a form of perispinal administration, and, in certain clinical circumstances may be the delivery method of choice, despite its greater difficulty and greater risk.

Epidural needle injection may be accomplished by percutaneous introduction of the needle carried through an intact ligamentum flavum to reach the epidural space. Gaps in the ligamentum flavum, including recently disclosed midline gaps, facilitate epidural delivery of etanercept to the epidural space after more superficial interspinous perispinal delivery. Local perispinal administration also has the advantage of providing a depot of therapeutic medication in the surrounding tissue, which will provide therapeutic levels of medication to the treatment site for a prolonged period of time. This decreases the necessity for another injection of medication. Additionally, administering medication locally limits the exposure of the medication to the systemic circulation, thereby decreasing renal and hepatic elimination of the medication, and decreasing exposure of the medication to systemic metabolism. All of these factors tend to increase the therapeutic half-life of the administered cytokine antagonist. Taken together, all of these forms of localized anatomic administration have significant clinical advantages over the various forms of systemic administration customarily used to deliver etanercept. The usual and customary route of administration for etanercept is systemically, by subcutaneous administration in the abdomen, thigh, or forearm. Intravenous administration of etanercept is another systemic route, as is intramuscular etanercept when etanercept is given at a site remote from the spine, such as the deltoid or gluteal region.

For the sake of this invention, the following definitions also apply: perilesional is defined as in anatomic proximity to the site of the pathologic process being treated; and peridural is defined as in anatomic proximity to the dura of the spinal cord, but specifically excluding intrathecal injection. The "interspinous route" for the purposes of this patent, is defined as parenteral injection through the skin in or near the midline, in the interspace between two spinous processes, to deliver etanercept in anatomic proximity to the epidural space and the vertebral venous plexus.
 

Claim 1 of 31 Claims

1. A method for delivering a TNF antagonist to the brain of a human for treating Alzheimer's related dementia, comprising administering the TNF antagonist etanercept parenterally into the perispinal space of said human without direct intrathecal injection, and thereafter positioning said human in a Trendelenburg position, for delivery of said TNF antagonist etanercept to the brain via the human's vertebral venous system (VVS).

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